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| Status |
Public on Mar 20, 2015 |
| Title |
Analysis of mRNA profiles distinguishes proneural (PN) glioma stem cells (GSC) from mesenchymal (Mes) GSCs |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Tumor heterogeneity of high-grade glioma (HGG) is recognized by four clinically relevant subtypes based on core gene signatures. However, molecular signaling in glioma stem cells (GSCs) in individual HGG subtypes is poorly characterized. Here we identified and characterized two mutually exclusive GSC subtypes with distinct dysregulated signaling pathways. Analysis of mRNA profiles distinguished proneural (PN) from mesenchymal (Mes) GSCs and revealed a pronounced correlation with the corresponding PN or Mes HGGs. Mes GSCs displayed more aggressive phenotypes in vitro and as intracranial xenografts in mice. Further, Mes GSCs were markedly resistant to radiation compared with PN GSCs. The glycolytic pathway, comprising aldehyde dehydrogenase (ALDH) family genes and in particular ALDH1A3, were enriched in Mes GSCs. Glycolytic activity and ALDH activity were significantly elevated in Mes GSCs but not in PN GSCs. Expression of ALDH1A3 was also increased in clinical HGG compared with low-grade glioma or normal brain tissue. Moreover, inhibition of ALDH1A3 attenuated the growth of Mes but not PN GSCs. Last, radiation treatment of PN GSCs up-regulated Mes-associated markers and downregulated PN-associated markers, whereas inhibition of ALDH1A3 attenuated an irradiation-induced gain of Mes identity in PN GSCs. Taken together, our data suggest that two subtypes of GSCs, harboring distinct metabolic signaling pathways, represent intertumoral glioma heterogeneity and highlight previously unidentified roles of ALDH1A3-associated signaling that promotes aberrant proliferation of Mes HGGs and GSCs. Inhibition of ALDH1A3- mediated pathways therefore might provide a promising therapeutic approach for a subset of HGGs with the Mes signature.
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| Overall design |
HGG tumors are composed of heterogeneous tumor cell populations including glioma stem cells (GSC) which may contribute to the therapeutic resistance of HGG. GSCs were derived from 19 high-grade glioma (HGG) samples and a fetal neural progenitor (16wf). We observed two phenotypically different GSC cultures with distinct morphologies. One set of GSC cultures (n = 10) displayed round neurosphere-like floating aggregates (cluster 1), and the other set (n = 9) formed irregular-shaped floating aggregates with some adherent cells on the bottom of the culture dish (cluster 2). Cluster 2 GSCs showed more aggressive phenotypes than cluster 1 GSCs in vitro and in vivo. We performed transcriptome microarray analysis of 27 GSC samples (triplicate samples) from nine patient-derived GSC cultures, five glioma cell lines as well as normal human astrocytes and fetal neural progenitors (16wf) as the normal controls.
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| Contributor(s) |
Mao P, Joshi K, Li J, Kim S, Li P, Santana-Santos L, Luthra S, Chandran UR, Benos PV, Smith L, Wang M, Hu B, Cheng S, Sobol RW, Nakano I |
| Citation(s) |
23650391, 26859459, 26251826, 27698350, 34806016 |
| Submission date |
Mar 19, 2015 |
| Last update date |
Nov 30, 2021 |
| Contact name |
Uma Chandran |
| E-mail(s) |
chandran@pitt.edu
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| Phone |
412-648-9326
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| Organization name |
University of Pittsburgh
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| Department |
BioMedical Informatics
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| Street address |
5150 Center Ave
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| City |
Pittsburgh |
| State/province |
PA |
| ZIP/Postal code |
15232 |
| Country |
USA |
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| Platforms (1) |
| GPL13667 |
[HG-U219] Affymetrix Human Genome U219 Array |
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| Samples (48)
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| GSM1638624 |
157, biological replicate 1 |
| GSM1638625 |
157, biological replicate 2 |
| GSM1638626 |
157, biological replicate 3 |
| GSM1638627 |
16WF, biological replicate 1 |
| GSM1638628 |
16WF, biological replicate 2 |
| GSM1638629 |
16WF, biological replicate 3 |
| GSM1638630 |
528, biological replicate 1 |
| GSM1638631 |
528, biological replicate 2 |
| GSM1638632 |
528, biological replicate 3 |
| GSM1638633 |
816, biological replicate 1 |
| GSM1638634 |
816, biological replicate 2 |
| GSM1638635 |
816, biological replicate 3 |
| GSM1638636 |
83, biological replicate 1 |
| GSM1638637 |
83, biological replicate 2 |
| GSM1638638 |
83, biological replicate 3 |
| GSM1638639 |
84, biological replicate 1 |
| GSM1638640 |
84, biological replicate 2 |
| GSM1638641 |
84, biological replicate 3 |
| GSM1638642 |
AC17, biological replicate 1 |
| GSM1638643 |
AC17, biological replicate 2 |
| GSM1638644 |
AC17, biological replicate 3 |
| GSM1638645 |
AC20, biological replicate 1 |
| GSM1638646 |
AC20, biological replicate 2 |
| GSM1638647 |
AC20, biological replicate 3 |
| GSM1638648 |
ASTROCYTE, biological relicate 1 |
| GSM1638649 |
ASTROCYTE, biological relicate 2 |
| GSM1638650 |
ASTROCYTE, biological relicate 3 |
| GSM1638651 |
ASTROCYTE, biological relicate 4 |
| GSM1638652 |
ASTROCYTE, biological relicate 5 |
| GSM1638653 |
LN428, biological replicate 1 |
| GSM1638654 |
LN428, biological replicate 2 |
| GSM1638655 |
LN428, biological replicate 3 |
| GSM1638656 |
LN444-AA |
| GSM1638657 |
LN444 |
| GSM1638658 |
MD13, biological replicate 1 |
| GSM1638659 |
MD13, biological replicate 2 |
| GSM1638660 |
MD13, biological replicate 3 |
| GSM1638661 |
MD30, biological replicate 1 |
| GSM1638662 |
MD30, biological replicate 2 |
| GSM1638663 |
MD30, biological replicate 3 |
| GSM1638664 |
T98G-untreated, biological replicate 1 |
| GSM1638665 |
T98G-untreated, biological replicate 2 |
| GSM1638666 |
T98G-untreated, biological replicate 3 |
| GSM1638667 |
U373 |
| GSM1638668 |
U87 |
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| Relations |
| BioProject |
PRJNA278898 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE67089_RAW.tar |
104.4 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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